Stem cell milestones for regenerative medicine

Philippa Brice

15 September 2014

In separate news this week, researchers have successfully ‘reset’ human pluripotent stem cells to an embryonic-like state; and a woman has received the world’s first transplant of induced pluripotent stem (iPS) cells.

Returning stem cells to the starting line

Scientists from the Wellcome Trust-MRC Cambridge Stem Cell Institute (CSCI) have induced cells to revert to a developmental stage equivalent to that of a 7-9 day old embryo. It was already possible to create iPS cells, but there have previously been limitations to this pluripotency, with cells effectively having reverted to a slightly later stage in the cellular differentiation process than has now been achieved.

Writing in the journal Cell, the researchers say they achieved stable reversion to this earlier state of pluripotency by what is termed ‘rewiring of the transcription factor circuitry’ involved in the control of gene expression – induced short-term expression of the transcription factors NANOG and Klf2  followed by ongoing inhibition of ERK and protein kinase C. The treated cells reportedly reverted to a naïve state capable of developing into any cell type, with stable genomic sequences and largely erased DNA methylation (epigenetic) patterns. It was previously possible to achieve this with mouse cells using a different protein, but not human ones. Introduction of the NANOG and KLF2 genes was said to effectively ‘reboot’ the network of genetic control.

The researchers say their findings demonstrate the feasibility of creating and maintaining ‘ground-state pluripotency in human cells’, with potential application in the development of cellular therapies, diagnostics and drug safety screening tools.

Pluripotent stem cell transplants

Meanwhile, a Japanese woman has become the world’s first recipient of cells derived from iPS cells.

A team of specialists led by Dr Yasuo Kurimoto of the Kobe City Medical Center General Hospital transplanted retinal pigment epithelium cells into an eye of the 70-year old woman as a treatment for age-related macular degeneration (AMD). The transplanted cells were produced from the patient’s own skin cells by RIKEN Center for Developmental Biology (CDB) expert Dr Masayo Takahashi, who created iPS cells, then programmed them to differentiate into specialised retinal cells.

Whilst no clinical benefit has been reported (or is necessarily expected) for the procedure, it is an important experiment in terms of safety in humans; the overriding concern is that stem cell transplants might result in tumours. Demonstration of efficacy in arresting further deterioration of the retinal cells would also be a crucial proof-of-principle.

Commenting on the transplant, Takahashi said it was a “momentous first step toward regenerative medicine using iPS cells”, whilst Kurimoto expressed thanks to the late Yoshiki Sasai, RIKEN CDB deputy director, saying: “This project could not have existed without the late Yoshiki Sasai’s research, which led the way to differentiating retinal tissue from stem cells”.

A fresh start for Japanese regenerative medicine?

Sasai faced widespread censure for his role as senior author of a paper published earlier this year setting out a revolutionary new method for the creation of stem cells; despite widespread enthusiasm for this new method, other researchers were unable to reproduce the results, leading to accusations of fraud, and the eventual retraction of the paper at the request of both Sasai and first author Haruko Obokata.

The RIKEN committee appointed to investigate the situation concluded that Obokata was guilty of scientific misconduct with respect to some of the figures in the paper, and condemned Sasai’s failure to identify these shortcomings and the reproducibility of the method before publication. Tragically, Sasai committed suicide last month.

Hopefully, the cloud left hanging over Japanese stem cell research is now lifting, and the benefits of heavy investment in the field by the Japanese Government as well as that of the UK are starting to pay off; as well as the clinical trial of iPS cells, the CSCI research in Cambridge, England was led by Japanese Dr Yasuhiro Takashima, supported by the Japan Science and Technology Agency.